Process for synthesizing highly optically active 1,3-disubstituted allenes

ABSTRACT

The present invention relates to a process for efficiently synthesizing highly optically active 1,3-disubstituted allenes, i.e., a one-step process for preparing highly optically active 1,3-disubstituted allenes by using a functionalized terminal alkyne, an aldehyde and a chiral α,α-diphenyl prolinol as reactants under the catalysis of a divalent copper salt. The operation of the process is simple, and the raw materials and reagents are readily available. The process has a broad-spectrum of substrates and a good compatibility for a wide variety of functional groups such as glycosidic units, primary alcohols, secondary alcohols, tertiary alcohols, amides, malonates, etc., and does not require the protection for the functional groups. The obtained axially chiral allene has a moderate to high yield and a good diastereoselectivity or enantioselectivity.

TECHNICAL FIELD

The present invention relates to a chemical synthetic process,particularly to a process for synthesizing highly optically active1,3-disubstituted allenes.

BACKGROUND

Due to the unique structure and active reactive performances of allenecompounds as well as their more and more important role played in theorganic syntheses, the allene chemistry has attracted more and moreattentions (S. Yu, S. Ma, Angew. Chem., Int. Ed. 2012, 51, 3074; M. A.Tius, Chem. Soc. Rev. 2014, 43, 2979; J. L. Bras, J. Muzart, Chem. Soc.Rev. 2014, 43, 3003; S. Kitagaki, F. Inagaki, C. Mukai, Chem. Soc. Rev.2014, 43, 2956; M. P. Muñoz, Chem. Soc. Rev. 2014, 43, 3164; C. S.Adams, C. D. Weatherly, E. G. Burke, J. M. Schomaker Chem. Soc. Rev.2014, 43, 3136; R. Zimmer, H. U. Reissig, Chem. Soc. Rev., 2014, 43,2888; m) W. Yang, A. S. K. Hashmi, Chem. Soc. Rev., 2014, 43, 2941; B.Alcaide, P. Almendros, C. Aragoncillo, Chem. Soc. Rev. 2014, 43, 3106;T. Cañeque, F. M. Truscott, R. Rodriguez, G. Maestri, M. Malacria, Chem.Soc. Rev. 2014, 43, 2916; F. López, J. L. Mascareñas, Chem. Soc. Rev.2014, 43, 2904; Z. Wang, X. Xu, O. Kwon, Chem. Soc. Rev. 2014, 43,2927). Therefore, how to simply and efficiently synthesize variousallene compounds, especially 1,3-disubstituted allenes having an axialchirality activity, has become one of the issues of increasing concernto the chemists (L. K. Sydnes, Chem. Rev. 2003, 103, 1133; N. Krause, A.Hoffmann-Röder, Tetrahedron 2004, 60, 11671; K. M. Brummond, J. E.Deforrest, Synthesis 2007, 795; M. Ogasawara, Tetrahedron: Asymmetry2009, 20, 259; g) S. Yu, S. Ma, Chem. Commun., 2011, 47, 5384). Theearlier synthetic methods of optically active 1,3-substituted allenesrequire the use of hazardous chemicals such as n-butyl lithium or ethylmagnesium bromide and lithium aluminum hydride, and the operations areinconvenient, which were unbeneficial to the large scale synthesis(L.-I. Olsson, A. Claesson, Acta Chem. Scand. 1977, B31, 614; A.Claesson, L.-I. Olsson, J. Am. Chem. Soc. 1979, 101, 7302; R. A. Smith,R. L. White, A. Krantz, J. Med. Chem. 1988, 31, 1558; J.Stichler-Bonaparte, H. Kruth, R. Lunkwitz, C. Tschierske, Liebigs Ann.1996, 1375). Recently our team developed a series of processes forsynthesizing optically active 1,3-disubstituted allenes by usingterminal alkynes, aldehydes and chiral amines under the promotion of azinc salt or under the co-promotion of a zinc salt and a monovalentcopper salt. Although these processes have made great progress comparedto the traditional methods, there are still some shortcomings such as anarrow substrate range, the requirement of large amount of metallicsalts, going through a multi-step operation of the protection anddeprotection for some specific functional groups (J. Ye, S. Li, B. Chen,W. Fan, J. Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q.Yu, W. Yuan, S. Ma, Org. Lett. 2012, 14, 1346; J. Ye, W. Fan, S. Ma,Chem. Eur J. 2013, 19, 716; J. Ye, R. Lu, W. Fan, S. Ma, Tetrahedron2013, 69, 8959; R. Lü, J. Ye, T. Cao, B. Chen, W. Fan, W. Lin, J. Liu,H. Luo, B. Miao, S. Ni, X. Tang, N. Wang, Y. Wang, X. Xie, Q. Yu, W.Yuan, W. Zhang, C. Zhu, S. Ma, Org. Lett. 2013, 15, 2254).

The present invention overcomes all the drawbacks of the prior arts,which provides a one-step process for simply and efficiently preparinghighly optically active 1,3-disubstituted allenes by using a divalentcopper salt as the catalyst and using a terminal alkyne and chiralα,α-diphenyl prolinol as reactants.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a simple and efficientprocess for synthesizing highly optically active 1,3-disubstitutedallenes, i.e., a one-step process for preparing highly optically active1,3-disubstituted allenes by using a functionalized terminal alkyne, analdehyde and chiral α,α-diphenyl prolinol as reactants under thecatalysis of a divalent copper salt.

The object of the present invention is achieved by using the followingsolution:

The present invention discloses a process for efficiently synthesizinghighly optically active 1,3-disubstituted allenes, which uses afunctionalized terminal alkyne, an aldehyde and a chiral secondary amineas reactants under the catalysis of a divalent copper salt and therebyproduces a variety of functionalized axially chiral 1,3-disubstitutedallenes by the heated reaction in an organic solvent. The reaction has afollowing reaction equation:

wherein R¹ comprises a variety of functional groups such as glycosidicunits, primary alcohols, secondary alcohols, tertiary alcohols, amides,malonates, alkyl group or aryl group, and R² is an alkyl group or anaryl group.

As a further improvement, the present process comprises the followingsteps:

1) under nitrogen atmosphere, a divalent copper salt, a chiral secondaryamine, a terminal alkyne, an aldehyde and an organic solvent were addedin sequence into a reaction tube subjected to the anhydrous andanaerobic treatment, heating for reaction for 12-24 h;

2) after the completion of the reaction of step 1), raising the reactiontube from the oil bath, naturally returning to the room temperature,diluting with an organic solvent, transferring the liquid to aseparatory funnel, washing with dilute hydrochloric acid, separating theorganic phase, extracting the aqueous phase with the same organicsolvent, combining the organic phases, washing with saturated brine,drying with anhydrous sodium sulfate, filtering, concentrating andsubjecting to the column chromatography, so as to obtain the productaxially chiral allene.

As a further improvement, the present process uses a divalent coppersalt as catalyst, the catalyst is copper bromide, copper chloride,copper acetate, copper sulfate or copper triflate.

As a further improvement, the chiral secondary amine used in the presentinvention is (S)-3a or its enantiomers, and the structural variants(S)-3b and (S)-3c using (S)-3a as a template or their enantiomers.

As a further improvement, the organic solvent used in the presentinvention is 1,4-dioxane, toluene, benzene, chlorobenzene, p-xylene,o-xylene, m-xylene, or mesitylene.

The present invention overcomes the drawbacks of the traditionalmethods, which has the following advantages: (1) greatly reduces theamount of metallic salt catalyst used; (2) has a broader spectrum ofsubstrates and a good compatibility for functional groups, and does notrequire the protection for the functional groups; (3) the reaction hasan excellent diastereoselectivity or enantioselectivity; and (4) theproduct is easy to separate and purify.

The innovation point of the present invention lies in developing asimple and efficient process for synthesizing highly optically active1,3-disubstituted allenes, and for the first time discovering that adivalent copper salt can directly catalyzing the three-componentreaction consisting of a terminal alkyne, an aldehyde and a chiralsecondary amine, and that the reaction has a good selectivity whereinboth de value and ee value are greater than 90%.

PREFERRED EMBODIMENTS OF THE INVENTION

The following examples are given for further illustrating the specificsolutions of the present invention.

EXAMPLE 1

Wherein “equiv” refers to equivalent; “de” refers to diastereomericexcess; “cc” refers to enantiomeric excess.

To a flame-dried Schlenk tube were added CuBr₂ (44.9 mg, 0.2 mmol), 1a(387.0 mg, 1.0 mmol), (S)-3a (304.5 mg, 1.2 mmol), and 2a (180.1 mg, 1.4mmol)/dioxane (3.0 mL) sequentially under nitrogen atmosphere. TheSchlenk tube was then equipped with a condenser and the outlet connectedto the vacuum line with a nitrogen flow was closed. The reaction wascomplete after being stirred at 130° C. for 16 h as monitored by TLC(eluent: petroleum ether/ethyl acetate=3/1). Then the resulting mixturewas diluted with ethyl acetate (30 mL), and washed with an aqueoussolution of hydrochloric acid (v/v=10%). The organic layer wasseparated, and the aqueous layer was extracted with ethyl acetate (20mL). The combined organic layer was washed with brine and dried overanhydrous Na₂SO₄. After filtration and evaporation, the residue waspurified by chromatography (eluent: petroleum ether/ethyl acetate=3/1)on silica gel to afford (R_(a))-4aa (246.5 mg, 49%) as a liquid: 98% de(HPLC conditions: Chiralcel AS-H column, hexane/i-PrOH=95/5, 0.3 mL/min,λ=214 nm, t_(R)(major)=24.9 min, t_(R)(minor)=26.8 min); [α]_(D)²⁰=−32.2 (c=1.07, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.28-4.95 (m, 5 H),4.64 (d, J=7.8 Hz, 1 H), 4.35-4.24 (m, 2 H), 4.18-4.07 (m, 2 H),3.74-3.63 (m, 1 H), 2.09 (s, 3 H, Me), 2.05 (s, 3 H, Me), 2.03 (s, 3 H,Me), 2.01 (s, 3 H, Me), 2.12-1.94 (m, 2 H, CH₂), 1.48-1.20 (m, 10 H,CH₂×5), 0.89 (t, J=6.9 Hz, 3 H, Me); ¹³C NMR (75 Hz, CDCl₃) δ 205.4,170.5, 170.2, 169.3, 169.2, 98.8, 92.1, 87.2, 72.8, 71.6, 71.0, 68.2,67.8, 61.7, 31.7, 28.98, 28.95, 28.9, 28.3, 22.5, 20.6, 20.52, 20.45,20.4, 13.9; IR (neat) ν (cm⁻¹) 2928, 2856, 1963, 1757, 1435, 1370, 1226,1165, 1041; MS (ESI, m/z) 521 (M+Na⁺), 516 (M+NH₄ ⁺); Anal. Calcd. forC₂₅H₃₈O₁₀ (%): C, 60.23; H, 7.68; Found: C, 60.21; H, 7.37.

EXAMPLE 2

Following the procedure of Example 1. The reaction of CuBr₂ (89.3 mg,0.4 mmol), 1a (772.5 mg, 2.0 mmol), (R)-3a (607.6 mg, 2.4 mmol), and 2a(360.6 mg, 2.8 mmol) in dioxane (6.0 mL) afforded (S_(a))-4aa (508.2 mg,51%) (eluent: petroleum ether/ethyl acetate=3/1) as a liquid: 98% de(HPLC conditions: Chiralcel AS-H column, hexane/i-PrOH=95/5, 0.4 mL/min,λ=214 nm, t_(R)(minor)=35.5 min, t_(R)(major)=36.5 min); [α]_(D)²⁰=+36.8 (c=0.975, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.28-4.95 (m, 5 H),4.64 (d, J=7.8 Hz, 1 H), 4.34-4.25 (m, 2 H), 4.18-4.07 (m, 2 H),3.75-3.66 (m, 1 H), 2.08 (s, 3 H, Me), 2.04 (s, 3 H, Me), 2.03 (s, 3 H,Me), 2.00 (s, 3 H, Me), 2.12-1.95 (m, 2 H, CH₂), 1.48-1.18 (m, 10 H,CH₂×5), 0.88 (t, J=6.6 Hz, 3 H, Me); ¹³C NMR (75 Hz, CDCl₃) δ 205.1,170.3, 169.9, 169.1, 169.0, 98.7, 92.0, 87.1, 72.6, 71.5, 70.9, 68.1,67.5, 61.6, 31.5, 28.8, 28.7, 28.1, 22.3, 20.39, 20.35, 20.3, 13.8; IR(neat) ν (cm⁻¹) 2929, 2857, 1962, 1759, 1435, 1367, 1227, 1166, 1040; MS(ESI, m/z) 516 (M+NH₄ ⁺); Anal. Calcd. for C₂₅H₃₈O₁₀ (%): C, 60.23; H,7.68; Found: C, 60.61; H, 7.71.

EXAMPLE 3

Following the procedure of Example 1. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1a (388.1 mg, 1.0 mmol), (S)-3a (303.3 mg, 1.2 mmol), and 2b(168.8 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ab (273.0 mg,55%) (eluent: petroleum ether/ethyl acetate=2.5/1) as a liquid: 97% de(HPLC conditions: Chiralcel IA-H column, hexane/i-PrOH=95/5, 1.0 mL/min,λ=214 nm, t_(R)(major)=16.4 min, t_(R)(minor)=23.0 min); [α]_(D)²⁰=−30.4 (c=1.405, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.39-7.19 (m, 5 H,ArH), 5.50-5.37 (m, 1 H), 5.22-5.11 (m, 2 H), 5.06 (t, J=9.6 Hz, 1 H),4.95 (t, J=8.9 Hz, 1 H), 4.35 (d, J=7.8 Hz, 1 H), 4.32-4.19 (m, 2 H),4.13-4.02 (m, 2 H), 3.55-3.29 (m, 3 H), 2.07 (s, 3 H, Me), 2.029 (s, 3H, Me), 2.026 (s, 3 H, Me), 2.00 (s, 3 H, Me); ¹³C NMR (75 Hz, CDCl₃) δ205.7, 170.4, 170.0, 169.15, 169.06, 139.2, 128.34, 128.28, 126.3, 98.2,91.5, 88.0, 72.5, 71.3, 70.8, 68.0, 67.0, 61.5, 34.7, 20.5, 20.42,20.35; IR (neat) ν (cm⁻¹) 3063, 3028, 2945, 2884, 1964, 1756, 1602,1495, 1450, 1433, 1370, 1226, 1165, 1041; MS (ESI, m/z) 529 (M+K⁺), 513(M+Na⁺), 508 (M+NH₄ ⁺); Anal. Calcd. for C₂₅H₃₀O₁₀ (%): C, 61.22; H,6.16; Found: C, 61.32; H, 6.03.

EXAMPLE 4

Following the procedure of Example 1. The reaction of CuBr₂ (44.7 mg,0.2 mmol), 1a (386.1 mg, 1.0 mmol), (S)-3a (303.5 mg, 1.2 mmol), and 2c(187.6 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ac (253.4 mg,50%) (eluent: petroleum ether/ethyl acetate=2.5/1) as a liquid: 99% de(HPLC conditions: Chiralcel OD-H column, hexane/i-PrOH=90/10, 1.0mL/min, λ=214 nm, t_(R)(major)=13.1 min, t_(R)(minor)=19.3 min); [α]_(D)²⁰=−37.7 (c=1.32, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.15 (m, 5 H),5.31-4.95 (m, 5 H, ArH), 4.57 (d, J=8.1 Hz, 1 H), 4.32-4.18 (m, 2 H),4.16-4.01 (m, 2 H), 3.70-3.61 (m, 1 H), 2.74 (t, J=7.7 Hz, 2 H),2.40-2.28 (m, 2 H), 2.07 (s, 3 H, Me), 2.03 (s, 3 H, Me), 2.02 (s, 3 H,Me), 2.00 (s, 3 H, Me); ¹³C NMR (75 Hz, CDCl₃) δ 205.3, 170.5, 170.2,169.3, 169.2, 141.2, 128.4, 128.2, 125.9, 99.2, 91.5, 87.9, 72.8, 71.7,71.2, 68.3, 67.7, 61.8, 35.1, 30.0, 20.59, 20.56, 20.49, 20.47; IR(neat) ν (cm⁻¹) 3063, 3024, 2942, 2861, 1964, 1757, 1603, 1496, 1453,1432, 1369, 1225, 1165, 1041; MS (ESI, m/z) 527 (M+Na⁺), 522 (M+NH₄ ⁺);Anal. Calcd. for C₂₆H₃₂O₁₀ (%): C, 61.90; H, 6.39; Found: C, 61.41; H,6.25. HRMS calcd. for C₂₆H₃₆NO₁₀ (M+NH₄ ⁺): 522.2334; Found: 522.2322.

EXAMPLE 5

Following the procedure of Example 1. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1a (385.4 mg, 1.0 mmol), (S)-3a (304.1 mg, 1.2 mmol), and 2d(121.2 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ad (245.2 mg,54%) (eluent: petroleum ether/ethyl acetate=3/1) as a solid: 97% de(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 1.0 mL/min,λ=214 nm, t_(R)(minor)=17.6 min, t_(R)(major)=18.9 min); [α]_(D)²⁰=−26.7 (c=1.00, CHCl₃); m.p. 68-69° C. (DCM/n-hexane); ¹H NMR (300MHz, CDCl₃) δ 5.28-4.95 (m, 5 H), 4.63 (d, J=8.1 Hz, 1 H), 4.36-4.21 (m,2 H), 4.20-4.04 (m, 2 H), 3.73-3.61 (m, 1 H), 2.09 (s, 3 H, Me), 2.06(s, 3 H, Me), 2.04 (s, 3 H, Me), 2.02 (s, 3 H, Me), 2.17-1.87 (m, 2 H,CH₂), 1.76-1.59 (m, 1 H, CH), 0.94 (d, J=6.6 Hz, 6 H, Me×2); ¹³C NMR (75Hz, CDCl₃) δ 205.9, 170.5, 170.2, 169.23, 169.16, 98.8, 90.5, 86.5,72.7, 71.6, 71.0, 68.1, 67.8, 61.7, 37.8, 28.1, 22.0, 21.9, 20.54,20.51, 20.44, 20.42; IR (KBr) ν (cm⁻¹) 2957, 2871, 1964, 1757, 1434,1369, 1226, 1165, 1041; MS (ESI, m/z) 479 (M+Na⁺), 474 (M+NH₄ ⁺); Anal.Calcd. for C₂₂H₃₂O₁₀ (%): C, 57.88; H, 7.07; Found: C, 57.89; H, 7.08.

EXAMPLE 6

Following the procedure of Example 1. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1a (388.5 mg, 1.0 mmol), (5)-3a (305.5 mg, 1.2 mmol), and 2e(157.5 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ae (275.1 mg,57%) (eluent: petroleum ether/ethyl acetate=3/1) as a solid: 99% de(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 1.0 mL/min,λ=214 nm, t_(R)(minor)=16.4 min, t_(R)(major)=19.1 min); [α]_(D)²⁰=(c=0.92, CHCl₃); m.p. 102-103° C. (DCM/n-hexane); ¹H NMR (300 MHz,CDCl₃) δ 5.27-4.96 (m, 5 H), 4.66 (d, J=8.1 Hz, 1 H), 4.36-4.22 (m, 2H), 4.19-4.05 (m, 2 H), 3.72-3.63 (m, 1 H), 2.09 (s, 3 H, Me), 2.05 (s,3 H, Me), 2.03 (s, 3 H, Me), 2.01 (s, 3 H, Me), 2.22-1.89 (m, 1 H, CH),1.81-1.60 (m, 5 H, CH₂×2 and one proton of CH₂), 1.40-1.00 (m, 5 H,CH₂×2 and one proton of CH₂); ¹³C NMR (75 Hz, CDCl₃) δ 204.3, 170.4,170.0, 169.2, 169.1, 98.7, 98.0, 88.1, 72.7, 71.5, 71.0, 68.1, 67.8,61.6, 36.6, 32.8, 32.6, 25.8, 25.6, 20.5, 20.42, 20.36; IR (KBr) ν(cm⁻¹) 2925, 2851, 1965, 1741, 1447, 1412, 1380, 1287, 1260, 1227, 1171,1115, 1094, 1058, 1036; MS (ESI, m/z) 505 (M+Na⁺), 500 (M+NH₄ ⁺); Anal.Calcd. for C₂₄H₃₄O₁₀ (%): C, 59.74; H, 7.10; Found: C, 59.80; H, 7.04.

EXAMPLE 7

Following the procedure of Example 1. The reaction of CuBr₂ (44.7 mg,0.2 mmol), 1a (384.2 mg, 1.0 mmol), (S)-3a (305.5 mg, 1.2 mmol), and 2f(101.4 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4af (233.9 mg,53%) (eluent: petroleum ether/ethyl acetate=2.5/1) as a liquid: 99% de(HPLC conditions: Chiralcel IA-H column, hexane/i-PrOH=95/5, 1.0 mL/min,λ=214 nm, t_(R)(minor)=15.1 min, t_(R)(major)=16.1 min); [α]_(D)²⁰=−23.1 (c=1.08, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.30-5.14 (m, 3 H),5.10 (t, J=9.6 Hz, 1 H), 5.01 (dd, J₁=9.6 Hz, J₂=8.1 Hz, 1 H), 4.66 (d,J=7.8 Hz, 1 H), 4.36-4.24 (m, 2 H), 4.17-4.07 (m, 2 H), 3.72-3.64 (m, 1H), 2.40-2.24 (m, 1 H, CH), 2.09 (s, 3 H, Me), 2.05 (s, 3 H, Me), 2.03(s, 3 H, Me), 2.01 (s, 3 H, Me), 1.03 (d, J=6.6 Hz, 6 H, Me×2); ¹³C NMR(75 Hz, CDCl₃) δ 204.0, 170.5, 170.2, 169.3, 169.2, 99.5, 98.7, 88.5,72.8, 71.6, 71.1, 68.2, 67.9, 61.8, 27.5, 22.3, 22.2, 20.6, 20.51,20.45, 20.4; IR (neat) ν (cm⁻¹) 2962, 2871, 1961, 1755, 1434, 1367,1227, 1165, 1040; MS (ESI, m/z) 460 (M+NH₄ ⁺); Anal. Calcd. forC₂₁H₃₀O₁₀ (%): C, 57.01; H, 6.83; Found: C, 57.05; H, 6.72.

EXAMPLE 8

Following the procedure of Example 1. The reaction of CuBr₂ (89.7 mg,0.4 mmol), 1a (386.8 mg, 1.0 mmol), (S)-3a (304.6 mg, 1.2 mmol), and 2g(196.8 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ag (277.3 mg,54%) (eluent: petroleum ether/ethyl acetate=2/1) as a liquid: 99% de(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 0.6 mL/min,λ=214 nm, t_(R)(major)=57.1 min, t_(R)(minor)=62.3 min); [α]_(D)²⁰=−111.8 (c=1.04, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.34-7.27 (m, 2 H,ArH), 7.25-7.19 (m, 2 H, ArH), 6.23 (dt, J₁=6.2 Hz, J₂=2.3 Hz, 1 H, oneproton of CH═C═CH), 5.65 (dd, J₁=13.8 Hz, J₂=6.3 Hz, 1 H, one proton ofCH═C═CH), 5.22 (t, J=9.5 Hz, 1 H), 5.14-4.97 (m, 2 H), 4.65 (d, J=7.8Hz, 1 H), 4.47-4.37 (m, 1 H), 4.29-4.18 (m, 2 H), 4.10 (dd, J₁=12.3 Hz,J₂=2.4 Hz, 1 H), 3.66-3.58 (m, 1 H), 2.03 (s, 3 H, Me), 2.02 (s, 3 H,Me), 2.00 (s, 3 H, Me), 1.99 (s, 3 H, Me); ¹³C NMR (75 Hz, CDCl₃) δ206.4, 170.3, 169.9, 169.1, 169.0, 132.8, 132.0, 128.7, 127.9, 99.2,94.9, 91.8, 72.7, 71.7, 71.1, 68.2, 66.6, 61.7, 20.4, 20.3; IR (neat) ν(cm⁻¹) 2956, 2925, 2869, 2849, 1953, 1755, 1492, 1456, 1429, 1376, 1224,1039; MS (ESI, m/z) 535 (M(³⁷Cl)+Na⁺), 533 (M(³⁵Cl)+Na⁺), 530(M(³⁷Cl)+NH₄ ⁺), 528 (M(³⁵Cl)+NH₄ ⁺); HRMS calcd. for C₂₄H₃₁ ³⁵ClNO₁₀(M(³⁵Cl)+NH₄ ⁺): 528.1631; Found: 528.1614.

EXAMPLE 9

Following the procedure of Example 1. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1b (498.9 mg, 1.0 mmol), (S)-3a (304.1 mg, 1.2 mmol), and 2e(156.9 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R)-4be (297.4 mg,50%) (eluent: petroleum ether/ethyl acetate=2.5/1) as a solid: 99% de(HPLC conditions: Chiralcel IA-H column, hexane/i-PrOH=80/20, 1.0mL/min, λ=214 nm, t_(R)(minor)=9.5 min, t_(R)(major)=10.9 min); [α]_(D)²⁰=−21.6 (c=0.97, CHCl₃); m.p. 117-118° C. (EtOAc/n-hexane); ¹H NMR (300MHz, CDCl₃) δ 7.78 (d, J=8.4 Hz, 2 H, ArH), 7.35 (d, J=8.1 Hz, 2 H,ArH), 5.27-5.08 (m, 3 H), 4.97-4.86 (m, 2 H), 4.58 (d, J=8.1 Hz, 1 H),4.27-4.17 (m, 1 H), 4.16-3.97 (m, 3 H), 3.77-3.68 (m, 1 H), 2.45 (s, 3H), 2.03 (s, 3 H, Me), 2.00 (s, 3 H, Me), 1.99 (s, 3 H, Me), 2.10-1.95(m, 1 H, CH), 1.82-1.59 (m, 5 H, CH₂×2 and one proton of CH₂), 1.40-0.98(m, 5 H, CH₂×2 and one proton of CH₂); ¹³C NMR (75 Hz, CDCl₃) δ 204.2,170.1, 169.3, 169.1, 145.0, 132.2, 129.8, 127.9, 98.7, 98.2, 88.2, 72.4,71.3, 70.8, 68.4, 67.9, 67.5, 36.6, 32.8, 32.7, 25.9, 25.7, 21.5, 20.47,20.42, 20.39; IR (KBr) ν (cm⁻¹) 2926, 2852, 1962, 1758, 1598, 1449,1369, 1245, 1218, 1178, 1040; MS (ESI, m/z) 612 (M+NH₄ ⁺); Anal. Calcd.for C₂₉H₃₈O₁₁S (%): C, 58.57; H, 6.44; Found: C, 58.81; H, 6.38.

EXAMPLE 10

Following the procedure of Example 1. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1c (472.5 mg, 1.0 mmol), (S)-3a (303.2 mg, 1.2 mmol), and 2e(158.1 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ce (256.2 mg,45%) (eluent: petroleum ether/ethyl acetate=1.5/1) as a liquid: 99% de(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 1.0 mL/min,λ=214 nm, t_(R)(minor)=27.3 min, t_(R)(major)=29.6 min); [α]_(D)²⁰=−38.9 (c=1.35, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.89 (t, J=5.4 Hz, 1H), 5.27-5.13 (m, 3 H), 5.02-4.85 (m, 2 H), 4.62 (d, J=8.1 Hz, 1 H),4.34-4.24 (m, 1 H), 4.18-4.07 (m, 1 H), 3.61-3.40 (m, 3 H), 2.23-2.11(m, 2 H), 2.06 (s, 3 H, Me), 2.05 (s, 3 H, Me), 2.00 (s, 3 H, Me),2.10-1.95 (m, 1 H, CH), 1.82-1.54 (in, 7 H, CH₂×3 and one proton ofCH₂), 1.39-1.00 (in, 1 3H, CH₂×6 and one proton of CH₂), 0.88 (t, J=6.6Hz, 3 H, Me); ¹³C NMR (75 Hz, CDCl₃) δ 204.3, 173.1, 170.1, 169.5,169.2, 99.2, 98.3, 88.3, 72.7, 72.4, 71.1, 68.7, 68.4, 38.8, 36.7, 36.5,32.9, 32.7, 31.5, 29.1, 28.9, 25.9, 25.7, 25.4, 22.5, 20.52, 20.47,13.9; IR (neat) ν (cm⁻¹) 3312, 2926, 2853, 1961, 1760, 1651, 1538, 1447,1373, 1248, 1220, 1165, 1050; MS (ESI, m/z) 604 (M+K⁺), 588 (M+Na⁺), 566(M+H⁺); Anal. Calcd. for C₃₀H₄₇NO₉ (%): C, 63.70; H, 8.37; N, 2.48;Found: C, 63.60; H, 8.39; N, 2.29.

EXAMPLE 11

Following the procedure of Example 1. The reaction of CuBr₂ (67.0 mg,0.3 mmol), 1d (457.3 mg, 1.0 mmol), (S)-3a (304.0 mg, 1.2 mmol), and 2e(157.3 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4de (255.0 mg,46%) (eluent: petroleum ether/ethyl acetate=2.5/1) as a liquid: 98% de(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=80/20, 0.5mL/min, λ=214 nm, t_(R)(minor)=12.2 min, t_(R)(major)=14.3 min); [α]_(D)²⁰=−30.0 (c=1.375, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.26-5.12 (m, 3 H),4.96 (dd, J₁=9.8 Hz, J₂=8.0 Hz, 1 H), 4.88 (t, J=9.5 Hz, 1 H), 4.52 (d,J=8.1 Hz, 1 H), 4.25 (ddd, J₁=11.4 Hz, J₂=6.3 Hz, J₃=2.7 Hz, 1 H), 4.06(ddd, J₁=11.7 Hz, =7.5 Hz, J₃=2.4 Hz, 1 H), 3.76 (s, 3 H, Me), 3.74 (s,3 H, Me), 3.67 (dd, J₁=9.6 Hz, J₂=5.1 Hz, 1 H), 3.52 (td, J₁=9.6 Hz,J₁=2.9 Hz, 1 H, CH), 2.30-2.19 (m, 1 H), 2.13-1.94 (m, 11 H), 1.81-1.60(m, 5 H, CH₂×2 and one proton of CH₂), 1.40-1.00 (m, 5 H, CH₂×2 and oneproton of CH₂); ¹³C NMR (75 Hz, CDCl₃) δ 204.1, 170.1, 169.5, 169.2,169.1, 169.0, 99.2, 98.1, 88.3, 72.6, 71.6, 71.1, 71.0, 68.1, 52.6,52.5, 47.4, 36.6, 32.8, 32.7, 30.2, 25.9, 25.7, 20.52, 20.49, 20.4; IR(neat) ν (cm⁻¹) 2927, 2852, 1961, 1755, 1436, 1367, 1245, 1218, 1159,1046; MS (ESI, m/z) 577 (M+Na⁺), 572 (M+NH₄ ⁺); Anal. Calcd. forC₂₇H₃₈O₁₂ (%): C, 58.47; H, 6.91; Found: C, 58.04; H, 6.68. HRMS calcd.for C₂₇H₄₂N O₁₂ (M+NH₄ ⁺): 572.2702; Found: 572.2688.

EXAMPLE 12

Following the procedure of Example 1. The reaction of CuBr₂ (67.3 mg,0.3 mmol), 1e (388.0 mg, 1.0 mmol), (S)-3a (303.7 mg, 1.2 mmol), and 2e(158.0 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ee (240.3 mg,50%) (eluent: petroleum ether/ethyl acetate=3/1) as a liquid: 96% de(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 1.0 mL/min,λ=214 nm, t_(R)(major)=20.0 min, t_(R)(minor)=23.5 min); [α]_(D)²⁰=−26.7 (c=1.24, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.40 (d, J=3.0 Hz, 1H), 5.27-5.13 (m, 3 H), 5.02 (dd, J₁=10.4 Hz, J₂=3.2 Hz, 1 H), 4.62 (d,J=8.1 Hz, 1 H), 4.37-4.27 (m, 1 H), 4.23-4.07 (m, 3 H), 3.89 (t, J=6.6Hz, 1 H), 2.16 (s, 3 H, Me), 2.09 (s, 3 H, Me), 2.06 (s, 3 H, Me), 1.99(s, 3 H, Me), 2.20-1.93 (m, 1 H, CH), 1.83-1.60 (m, 5 H, CH₂×2 and oneproton of CH₂), 1.40-0.99 (m, 5 H, CH₂×2 and one proton of CH₂); ¹³C NMR(75 Hz, CDCl₃) δ 204.3, 170.12, 170.09, 170.0, 169.2, 99.2, 98.0, 88.2,70.8, 70.4, 68.6, 67.8, 66.8, 61.1, 36.6, 32.8, 32.6, 25.8, 25.7, 20.5,20.43, 20.36; IR (neat) ν (cm⁻¹) 2926, 2852, 1961, 1754, 1449, 1370,1223, 1170, 1132, 1075, 1057; MS (ESI, m/z) 505 (M+Na⁺), 500 (M+NH₄ ⁺);Anal. Calcd. for C₂₄H₃₄O₁₀ (%): C, 59.74; H, 7.10; Found: C, 59.77; H,6.97.

EXAMPLE 13

Following the procedure of Example 1. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1f (400.8 mg, 1.0 mmol), (S)-3a (304.6 mg, 1.2 mmol), and 2e(157.2 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4fe (230.3 mg,46%) (eluent: petroleum ether/ethyl acetate=3/1) as a solid: 96% de(HPLC conditions: Chiralcel AS-H column, hexane/i-PrOH=95/5, 0.5 mL/min,λ=214 nm, t_(R)(minor)=23.0 min, t_(R)(major)=24.5 min); [α]_(D)²⁰=−47.9 (c=1.24, CHCl₃); m.p. 103-104° C. (EtOAc/n-hexane); ¹H NMR (300MHz, CDCl₃) δ 5.27-5.14 (m, 3 H), 5.14-5.01 (m, 2 H), 4.58 (d, J=9.9 Hz,1 H), 4.25 (dd, J₁=12.5 Hz, J₂=5.0 Hz, 1 H), 4.13 (dd, J₁=12.2 Hz,J₂=2.0 Hz, 1 H), 3.71-3.62 (m, 1 H), 3.35 (ddd, J₁=13.8 Hz, J₂=7.5 Hz,J₃=2.3 Hz, 1 H), 3.24 (ddd, J₁=13.8 Hz, J₂=6.5 Hz, J₃=3.0 Hz, 1 H), 2.08(s, 3 H, Me), 2.07 (s, 3 H, Me), 2.03 (s, 3 H, Me), 2.02 (s, 3 H, Me),2.12-1.94 (m, 1 H, CH), 1.82-1.60 (m, 5 H, CH₂×2 and one proton of CH₂),1.40-1.00 (m, 5 H, CH₂×2 and one proton of CH₂); ¹³C NMR (75 Hz, CDCl₃)δ 203.7, 170.5, 170.0, 169.2, 98.5, 88.8, 82.7, 75.7, 73.8, 69.7, 68.1,61.9, 37.2, 33.0, 32.9, 30.1, 25.9, 25.7, 20.6, 20.5, 20.4; IR (KBr) ν(cm⁻¹) 2926, 2852, 1953, 1756, 1448, 1371, 1225, 1040; MS (ESI, m/z) 516(M+NH₄ ⁺); Anal. Calcd. for C₂₄H₃₄O₉S (%): C, 57.81; H, 6.87; Found: C,58.03; H 6.82.

EXAMPLE 14

Following the procedure of Example 1. The reaction of CuBr₂ (44.7 mg,0.2 mmol), 1g (402.0 mg, 1.0 mmol), (S)-3a (306.1 mg, 1.2 mmol), and 2e(157.2 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ge (183.2 mg,37%) (eluent: petroleum ether/ethyl acetate=2.5/1) as a solid: 98% de(HPLC conditions: Chiralcel IC column, hexane/i-PrOH=96/4, 0.4 mL/min,λ=214 nm, t_(R)(minor)=76.6 min, t_(R)(major)=78.3 min); [α]_(D)²⁰=−47.8 (c=1.38, CHCl₃); m.p. 86-87° C. (DCM/n-hexane); ¹H NMR (300MHz, CDCl₃) δ 5.21 (t, J=9.5 Hz, 1 H), 5.14-4.94 (m, 4 H), 4.53 (d,J=8.1 Hz, 1 H), 4.28 (dd, J₁=12.3 Hz, J₂=4.8 Hz, 1 H), 4.13 (dd, J₁=12.3Hz, J₂=2.4 Hz, 1 H), 3.92 (dt, J₁=9.6 Hz, J₂=6.9 Hz, 1 H), 3.71 (ddd,J₁=10.1 Hz, J₂=4.8 Hz, J₁=2.4 Hz, 1 H), 3.55 (dt, J₁=9.6 Hz, J₂=7.2 Hz,1 H), 2.32-2.20 (m, 2 H, CH₂), 2.09 (s, 3 H, Me), 2.05 (s, 3 H, Me),2.03 (s, 3 H, Me), 2.01 (s, 3 H, Me), 2.13-1.88 (m, 1 H, CH), 1.80-1.58(m, 5 H, CH₂×2 and one proton of CH₂), 1.37-0.97 (m, 5 H, CH₂×2 and oneproton of CH₂); ¹³C NMR (75 Hz, CDCl₃) δ 203.2, 170.6, 170.2, 169.3,169.2, 100.7, 97.4, 87.4, 72.7, 71.6, 71.1, 69.7, 68.2, 61.8, 36.9,32.9, 32.8, 29.3, 26.0, 25.8, 20.6, 20.5, 20.4; IR (KBr) ν (cm⁻¹) 2926,2852, 1959, 1757, 1448, 1369, 1225, 1170, 1040; MS (ESI, m/z) 514 (M+NH₄⁺); Anal. Calcd. for C₂₅H₃₆O₁₀ (%): C, 60.47; H, 7.31; Found: C, 60.54;H, 7.25.

EXAMPLE 15

Following the procedure of Example 1. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1h (862.1 mg, 1.0 mmol), (S)-3a (304.4 mg, 1.2 mmol), and 2e(157.5 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R)-4he (456.7 mg,48%) (eluent: petroleum ether/ethyl acetate=1.5/1) as a syrup: 98% de(HPLC conditions: (Supercritical Fluid Chromatography) Chiralcel IAcolumn, CO₂/i-PrOH=80/20, 1.5 mL/min, λ=214 nm, t_(R)(minor)=8.3 min,t_(R)(major)=14.2 min); [α]_(D) ²⁰=−13.8 (c=1.21, CHCl₃); NMR (300 MHz,CDCl₃) δ 7.98-7.88 (m, 4 H, ArH), 7.84-7.78 (m, 2 H, ArH), 7.55-7.45 (m,2 H, ArH), 7.43-7.32 (m, 5 H, ArH), 7.28-7.20 (m, 2 H, ArH), 5.88 (t,J=9.6 Hz, 1 H), 5.51 (dd, J₁=9.6 Hz, J₂=8.1 Hz, 1 H), 5.41 (t, J=9.8 Hz,1 H), 5.26-5.12 (m, 3 H), 5.11-4.98 (m, 2 H), 4.94 (d, J=7.8 Hz, 1 H),4.65 (d, J=7.8 Hz, 1 H), 4.43-4.33 (m, 1 H), 4.29-4.12 (m, 2 H),4.10-3.97 (m, 3 H), 3.78 (dd, J=18.8 Hz, J=11.3 Hz, 1 H), 3.74-3.65 (m,1 H), 2.09 (s, 3 H, Me), 2.01 (s, 3 H, Me), 2.00 (s, 3 H, Me), 1.99 (s,3 H, Me), 2.12-1.85 (m, 1 H, CH), 1.79-1.57 (m, 5 H, CH₂×2 and oneproton of CH₂), 1.34-0.95 (m, 5 H, CH₂×2 and one proton of CH₂); ¹³C NMR(75 Hz, CDCl₃) δ 204.1, 170.3, 170.0, 169.2, 169.1, 165.5, 165.1, 164.8,133.4. 133.02, 132.99, 129.6, 129.54, 129.47, 129.1, 128.5, 128.4,128.3, 128.11, 128.05, 100.6, 99.2, 98.2, 88.2, 73.5, 72.8, 72.6, 71.6,71.5, 70.9, 69.5, 68.2, 68.0, 67.7, 61.6, 36.5, 32.8, 32.5, 25.8, 25.7,25.6, 20.5, 20.4, 20.3; IR (neat) ν (cm⁻¹) 3063, 2927, 2852, 1959, 1754,1739, 1602, 1452, 1369, 1284, 1251, 1224, 1176, 1094, 1069, 1037; MS(MALDI, m/z) 995 (M+K⁺) 979 (M+Na⁺); Anal. Calcd. for C₅₁H₅₆O₁₈ (%): C,64.01; H, 5.90; Found: C, 64.00; H, 5.80.

EXAMPLE 16

Following the procedure of Example 1. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1i (861.1 mg, 1.0 mmol), (5)-3a (304.2 mg, 1.2 mmol), and 2e(157.2 mg, 1.4 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ie (492.2 mg,51%) (eluent: petroleum ether/ethyl acetate=1.5/1) as a syrup: 98% de(HPLC conditions: (Supercritical Fluid Chromatography) Chiralcel IAcolumn, CO₂/i-PrOH=70/30, 1.5 mL/min, λ=214 nm, t_(R)(minor)=4.5 min,t_(R)(major)=6.1 min); [α]_(D) ²⁰=−13.5 (c=1.12, CHCl₃); ¹H NMR (300MHz, CDCl₃) δ 7.80-7.88 (m, 4 H, ArH), 7.85-7.78 (m, 2 H, ArH),7.55-7.20 (m, 9 H, ArH), 5.88 (t, J=9.8 Hz, 1 H), 5.51 (dd, J₁=9.8 Hz,J₂=8.0 Hz, 1 H), 5.46-5.36 (m, 2 H), 5.26 (dd, J₁=10.4 Hz, J₂=8.0 Hz, 1H), 5.20-5.12 (m, 2 H), 5.03 (dd, J₁=10.4 Hz, J₂=3.5 Hz, 1 H), 4.95 (d,J=7.8 Hz, 1 H), 4.62 (d, J=7.8 Hz, 1 H), 4.44-4.34 (m, 1 H), 4.25-3.97(m, 5 H), 3.92 (t, J=6.5 Hz, 1 H), 3.79 (dd, J₁=10.8 Hz, J₂=7.5 Hz, 1H), 2.110 (s, 3 H, Me), 2.107 (s, 3 H, Me), 2.01 (s, 3 H, Me), 1.98 (s,3 H, Me), 2.18-1.85 (m, 1 H, CH), 1.79-1.57 (m, 5 H, CH₂×2 and oneproton of CH₂), 1.34-0.95 (m, 5 H, CH₂×2 and one proton of CH₂); ¹³C NMR(75 Hz, CDCl₃) δ 204.1, 170.1, 170.0, 169.9, 169.2, 165.5, 165.1, 164.8,133.4, 133.02, 132.98, 129.5, 129.4, 129.0, 128.5, 128.4, 128.3, 128.1,128.0, 101.0, 99.2, 98.2, 88.2, 73.5, 72.8, 71.5, 70.7, 70.4, 69.5,68.4, 68.2, 67.7, 66.8, 61.0, 36.4, 32.8, 32.5, 25.8, 25.7, 25.6, 20.6,20.4, 20.33, 20.28; IR (neat) ν (cm¹) 3066, 2927, 2852, 1959, 1740,1602, 1451, 1370, 1281, 1255, 1218, 1177, 1090, 1069; MS (MALDI, m/z)979 (M+Na⁺); Anal. Calcd. for C₅₁H₅₆O (%): C, 64.01; H, 5.90; Found: C,64.04; H, 5.88.

EXAMPLE 17

To a flame-dried Schlenk tube with a polytetrafluoroethylene plug wereadded CuBr₂ (44.7 mg, 0.2 mmol), (S)-3a (253.1 mg, 1.0 mmol), 1j (84.3mg, 1.5 mmol)/dioxane (1.5 mL), and 2a (192.4 mg, 1.5 mmol)/dioxane (1.5mL) sequentially under nitrogen atmosphere. The Schlenk tube was thensealed by screwing the polytetrafluoroethylene plug tightly with theoutlet connected to the vacuum line with a nitrogen flow being closed.The reaction was complete after being stirred at 130° C. for 12 h asmonitored by TLC (eluent: petroleum ether/ethyl acetate=10/1). Then theresulting mixture was diluted with ether (30 mL), and washed with anaqueous solution of hydrochloric acid (3 M, 20 mL). The organic layerwas separated, and the aqueous layer was extracted with ether (20 mL).The combined organic layer was washed with brine and dried overanhydrous Na₂SO₄. After filtration and evaporation, the residue waspurified by chromatography (eluent: petroleum ether/ethyl acetate=8/1)on silica gel to afford (R_(a))-4ja (86.8 mg, 52%) as a liquid: 95% ee(HPLC conditions: Chiralcel AS-H column, hexane/i-PrOH=98/2, 0.6 mL/min,λ=214 nm, t_(R)(major)=10.9 min, t_(R)(minor)=11.8 min); [α]_(D)²⁰=−68.9 (c=1.01, CHCl₃); (reported value: 97% ee; [α]_(D) ²⁰=−66.1(c=1.03, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.37-5.24 (m, 2 H, CH═C═CH),4.17-4.07 (m, 2 H, OCH₂), 2.08-1.96 (m, 2 H, CH₂), 1.57 (t, J=4.8 Hz, 1H, OH), 1.48-1.20 (m, 10 H, CH₂×5), 0.88 (t, J=6.8 Hz, 3 H, Me); ¹³C NMR(75 MHz, CDCl₃) δ 202.9, 94.0, 91.7, 60.8, 31.8, 29.08, 29.07, 29.0,28.6, 22.6, 14.1; IR (neat) ν (cm⁻¹) 3336, 2956, 2926, 2855, 1963, 1465,1376, 1013; MS (EI): m/z (%) 168 (M⁺, 0.04), 55 (100). (reference: J.Ye, W. Fan, S. Ma, Chem. Eur. J. 2013, 19, 716).

EXAMPLE 18

Following the procedure of Example 17. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1j (84.6 mg, 1.5 mmol), (S)-3a (252.6 mg, 1.0 mmol), and 2h(150.2 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4jh (75.2 mg,54%) (eluent: petroleum ether/ethyl acetate=8/1) as a liquid: 94% ee(HPLC conditions: Chiralcel AS-H column, hexane/i-PrOH=100/1, 0.5mL/min, λ=214 nm, t_(R)(major)=18.9 min, t_(R)(minor)=20.0 min); [c]_(D)²⁰=−78.5 (c=1.11, CHCl₃) (reported value: 98% ee; [α]_(D) ²¹=−78.4(c=1.03, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.36-5.23 (m, 2 H, CH═C═CH),4.11 (dd, J₁=5.6 Hz, J₂=3.2 Hz, 2 H, OCH₂), 2.08-1.96 (m, 2 H, CH₂),1.80 (s, 1 H, OH), 1.49-1.21 (m, 6 H, CH₂×3), 0.89 (t, J=7.1 Hz, 3 H,Me); ¹³C NMR (75 MHz, CDCl₃) δ 203.0, 93.9, 91.6, 60.7, 31.2, 28.7,28.6, 22.4, 14.0; IR (neat) ν (cm⁻¹) 3337, 2957, 2927, 2857, 1963, 1466;MS (EI): m/z (%) 122 ((M−H₂O)⁺, 0.68), 55 (100). (reference: J. Ye, W.Fan, S. Ma, Chem. Eur. J. 2013, 19, 716).

EXAMPLE 19

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1j (84.2 mg, 1.5 mmol), (S)-3a (253.1 mg, 1.0 mmol), and 2c(201.4 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4jc (106.1 mg,61%) (eluent: petroleum ether/ethyl acetate=8/1 to petroleum ether/ethylacetate=5/1) as a liquid: 95% ee (HPLC conditions: Chiralcel AS-Hcolumn, hexane/i-PrOH=100/1, 1.0 mL/min, λ=214 nm, t_(R)(major)=22.4min, t_(R)(minor)=24.4 min); [α]_(D) ²⁰=−38.0 (c=0.89, CHCl₃) (reportedvalue: 96% ee; [α]_(D) ²°=−38.7 (c=1.05, CHCl₃)); ¹H NMR (300 MHz,CDCl₃) δ 7.36-7.13 (m, 5 H, ArH), 5.35-5.21 (m, 2 H, CH═C═CH), 4.04-3.90(m, 2 H, OCH₂), 2.83-2.64 (m, 2 H, CH₂), 2.46-2.24 (m, 2 H, CH₂), 1.62(s, 1 H, OH); ¹³C NMR (75 MHz, CDCl₃) δ 203.2, 141.4, 128.4, 128.2,125.9, 92.9, 92.1, 60.4, 35.0, 29.9; IR (neat) ν (cm⁻¹) 3366, 3084,3062, 3026, 2923, 2856, 1962, 1603, 1496, 1453, 1062, 1011; MS (EI) m/z(%): 174 (M⁺, 0.03), 156 ((M−H₂O)⁺, 41.67), 91 (100). (reference: J. Ye,W. Fan, S. Ma, Chem. Eur. J. 2013, 19, 716).

EXAMPLE 20

Following the procedure of Example 17. The reaction of CuBr₂ (44.6 mg,0.2 mmol), 1j (84.5 mg, 1.5 mmol), (S)-3a (253.6 mg, 1.0 mmol), and 2d(129.5 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4jd (57.3 mg,45%) (eluent: petroleum ether/ethyl acetate=8/1) as a liquid: 96% ee(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=200/1, 1.0mL/min, λ=214 nm, t_(R)(major)=18.7 min, t_(R)(minor)=22.0 min); [α]_(D)²⁰=−79.9 (c=0.955, CHCl₃) (reported value: 98% ee; [α]_(D) ²²=−80.3(c=1.01, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.35-5.19 (m, 2 H, CH═C═CH),4.11 (dd, J₁=5.9 Hz, J₂=2.9 Hz, 2 H, OCH₂), 1.97-1.89 (m, 2 H, CH₂),1.76-1.57 (m, 2 H, CH and OH), 0.93 (d, J=6.6 Hz, 6 H, Me×2); ¹³C NMR(75 MHz, CDCl₃) δ 203.6, 92.3, 91.0, 60.8, 38.1, 28.4, 22.12, 22.10; IR(neat) ν (cm⁻¹) 3338, 2956, 2926, 2893, 2870, 1962, 1466, 1384, 1367,1056, 1014; MS (EI) m/z (%): 126 (M⁺, 0.10), 108 ((M−H₂O)⁺, 31.12), 55(100). (reference: J. Ye, W. Fan, S. Ma, Chem. Eur J. 2013, 19, 716).

EXAMPLE 21

Following the procedure of Example 17. The reaction of CuBr₂ (44.7 mg,0.2 mmol), 1j (84.8 mg, 1.5 mmol), (5)-3a (252.2 mg, 1.0 mmol), and 2e(168.2 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4je (94.2 mg,62%) (eluent: petroleum ether/ethyl acetate=8/1) as a liquid: 94% ee(HPLC conditions: Chiralcel AS-H column, hexane/i-PrOH=98/2, 0.6 mL/min,λ=214 nm, t_(R)(major)=15.7 min, t_(R)(minor)=18.6 min); [α]_(D)²⁰=−98.1 (c=1.045, CHCl₃) (reported value: 99% ee; [α]_(D) ²²=−100.3(c=1.00, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.41-5.25 (m, 2 H, CH═C═CH),4.10 (dd, J₁=5.7 Hz, J₂=3.0 Hz, 2 H, OCH₂), 2.08-1.93 (m, 1 H, CH fromCy), 1.88-1.58 (m, 6 H, OH and five protons from Cy), 1.37-1.00 (m, 5 H,five protons from Cy); ¹³C NMR (75 MHz, CDCl₃) δ 201.8, 99.9, 92.6,60.8, 37.0, 33.0, 32.9, 26.0, 25.9; IR (neat) ν (cm⁻¹) 3331, 2924, 2851,1961, 1448, 1412, 1011; MS (EI) m/z (%): 152 (M⁺, 0.38), 134 ((M−H₂O)⁺,6.78), 55 (100). (reference: J. Ye, W. Fan, S. Ma, Chem. Eur J. 2013,19, 716).

EXAMPLE 22

Following the procedure of Example 17. The reaction of CuBr₂ (44.7 mg,0.2 mmol), 1k (126.8 mg, 1.5 mmol), (S)-3a (253.2 mg, 1.0 mmol), and 2e(168.6 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ke (89.3 mg,50%) (eluent: petroleum ether/ethyl acetate=12/1) as a liquid: 97% ee(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 0.6 mL/min,λ=214 nm, t_(R)(major)=8.9 min, t_(R)(minor)=10.2 min); [α]_(D) ²⁰=−99.2(c=0.97, CHCl₃) (reported value: 97% ee; [α]_(D) ²⁰=−99.5 (c=1.15,CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.38-5.26 (m, 2 H, CH═C═CH),2.07-1.92 (m, 1 H, CH from Cy), 1.84-1.59 (m, 6 H, OH and five protonsfrom Cy), 1.34 (s, 6 H, Me×2), 1.37-0.98 (m, 5 H, five protons from Cy);¹³C NMR (75 MHz, CDCl₃) δ 199.1, 102.1, 101.0, 69.5, 37.2, 33.02, 32.99,30.0, 29.9, 26.03, 26.00; IR (neat) ν (cm⁻¹) 3358, 2974, 2925, 2851,1960, 1448, 1373, 1361, 1228, 1149; MS (EI) m/z (%): 180 (M⁺, 0.29), 165(M−Me)⁺, 3.81), 59 (100). (reference: J. Ye, S. Li, B. Chen, W. Fan, J.Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu, W. Yuan,S. Ma, Org. Lett. 2012, 14, 1346).

EXAMPLE 23

Following the procedure of Example 17. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 11 (186.8 mg, 1.5 mmol), (S)-3a (252.7 mg, 1.0 mmol), and 2e(168.2 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4le (115.6 mg,53%) (eluent: petroleum ether/ethyl acetate=20/1) as a liquid: 98% ee(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=100/1, 0.5mL/min, λ=214 nm, t_(R)(major)=23.5 min, t_(R)(minor)=26.2 min); [α]_(D)²⁰=−106.6 (c=1.21, CHCl₃) (reported value: 96% ee; [α]_(D) ²⁰=−108.6(c=0.98, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.31 (d, J=4.2 Hz, 2 H,CH═C═CH), 2.08-1.90 (m, 1 H, CH from Cy), 1.87-1.40 (m, 15 H), 1.40-1.00(m, 6 H); ¹³C NMR (75 MHz, CDCl₃) δ 199.9, 101.3, 100.8, 70.4, 38.4,38.2, 37.2, 33.1, 33.0, 26.00, 25.97, 25.5, 22.4; IR (neat) ν (cm⁻¹)3373, 2926, 2851, 1960, 1448, 1347, 1262, 1242, 1146, 1056, 1034; MS(EI) m/z (%): 220 (M⁺, 0.69), 99 (100). (reference: J. Ye, S. Li, B.Chen, W. Fan, J. Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X.Xie, Q. Yu, W. Yuan, S. Ma, Org. Lett. 2012, 14, 1346).

EXAMPLE 24

Following the procedure of Example 17. The reaction of CuBr₂ (44.7 mg,0.2 mmol), (S)-1m (197.6 mg, 1.5 mmol), (S)-3a (252.7 mg, 1.0 mmol), and2e (168.3 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (S,R_(a))-4me(152.0 mg, 67%) (eluent: petroleum ether/ethyl acetate=12/1) as aliquid: >99% de, >99% ee (major isomer) (HPLC conditions: Chiralcel OD-Hcolumn, hexane/i-PrOH=98/2, 1.0 mL/min, λ=214 nm, t_(R)(major)=19.4 min;[α]_(D) ²⁰=−69.7 (c=1.24, CHCl₃) (reported value: 92% de, >99% ee;[α]_(D) ²⁰=−60.7 (c=1.02, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 7.42-7.21(m, 5 H, ArH), 5.47-5.38 (m, 1 H, one proton from HC═C═CH), 5.38-5.30(m, 1 H, one proton from HC═C═CH), 5.21 (d, J=5.4 Hz, 1 H, PhCH), 2.33(s, 1 H, OH), 2.07-1.91 (m, 1 H, CH from Cy), 1.80-1.56 (m, 5 H, fiveprotons from Cy), 1.35-0.96 (m, 5 H, five protons from Cy); ¹³C NMR (75MHz, CDCl₃) δ 201.2, 143.2, 128.3, 127.5, 126.0, 100.9, 96.9, 72.3,37.1, 32.9, 26.0, 25.9; IR (neat) ν (cm⁻¹) 3365, 3063, 3029, 2924, 2850,1960, 1599, 1489, 1449, 1015; MS (EI) m/z (%): 228 (M⁺, 2.53), 107(100). (reference: J. Ye, S. Li, B. Chen, W. Fan, J. Kuang, J. Liu, Y.Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu, W. Yuan, S. Ma, Org. Lett.2012, 14, 1346).

EXAMPLE 25

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), (R)-1m (198.5 mg, 1.5 mmol), (S)-3a (253.7 mg, 1.0 mmol), and2e (168.1 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R,R_(a))-4me(133.3 mg, 58%) (eluent: petroleum ether/ethyl acetate=12/1) as aliquid: 98% de, >99% ee (major isomer) (HPLC conditions: Chiralcel OD-Hcolumn, hexane/i-PrOH=98/2, 1.0 mL/min, λ=214 nm, t_(R)(major)=11.1 min;[α]_(D) ²⁰=−52.6 (c=0.98, CHCl₃) (reported value: 94% de, 97% ee;[α]_(D) ²⁰=−56.8 (c=0.98, CHCl₃)); NMR (300 MHz, CDCl₃) δ 7.40-7.29 (m,4 H, ArH), 7.29-7.21 (m, 1 H, ArH), 5.47-5.38 (m, 1 H, one proton fromHC═C═CH), 5.37-5.30 (m, 1 H, one proton from HC═C═CH), 5.18 (dd, J₁=5.9Hz, J₂=2.6 Hz, 1 H. PhCH), 2.30 (s, 1 H, OH), 2.07-1.93 (m, 1 H, CH fromCy), 1.80-1.56 (m, 5 H, five protons from Cy), 1.36-0.98 (m, 5 H, fiveprotons from Cy); ¹³C NMR (75 MHz, CDCl₃) δ 200.9, 143.1, 128.3, 127.5,126.1, 101.2, 97.0, 72.1, 37.1, 32.9, 26.0, 25.9; IR (neat) ν (cm⁻¹)3373, 3063, 3029, 2924, 2850, 1961, 1599, 1493, 1449, 1014; MS (EI) m/z(%): 228 (M⁺, 2.17), 107 (100). (reference: J. Ye, S. Li, B. Chen, W.Fan, J. Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu,W. Yuan, S. Ma, Org. Lett. 2012, 14, 1346).

EXAMPLE 26

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), (S)-1m (198.2 mg, 1.5 mmol), (R)-3a (253.8 mg, 1.0 mmol), and2e (167.9 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (S,S_(a))-4me(131.5 mg, 57%) (eluent: petroleum ether/ethyl acetate=12/1) as aliquid: 97% de, 99% ee (major isomer) (HPLC conditions: Chiralcel OD-Hcolumn, hexane/i-PrOH=98/2, 1.0 mL/min, λ=214 nm, t_(R)(minor)=11.7 min,t_(R)(major)=16.1 min; [α]_(D) ²⁰=+56.6 (c=1.34, CHCl₃) (reported value:89% de, >99% ee; [α]_(D) ²⁰=+54.7 (c=1.17, CHCl₃)); ¹H NMR (300 MHz,CDCl₃) δ 7.41-7.21 (m, 5 H, ArH), 5.47-5.38 (m, 1 H, one proton fromHC═C═CH), 5.37-5.30 (m, 1 H, one proton from HC═C═CH), 5.18 (dd, J₁=5.7Hz, J₂=2.4 Hz, 1 H, PhCH), 2.33 (s, 1 H, OH), 2.08-1.93 (m, 1 H, CH fromCy), 1.80-1.56 (m, 5 H, five protons from Cy), 1.36-0.98 (m, 5 H, fiveprotons from Cy); ¹³C NMR (75 MHz, CDCl₃) δ 200.9, 143.1, 128.3, 127.5,126.1, 101.2, 97.0, 72.1, 37.0, 32.9, 26.0, 25.9; IR (neat) ν (cm⁻¹)3365, 3062, 3029, 2924, 2850, 1961, 1602, 1492, 1449, 1014; MS (EI) m/z(%): 228 (M⁺, 1.93), 107 (100). (reference: J. Ye, S. Li, B. Chen, W.Fan, J. Kuang, J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu,W. Yuan, S. Ma, Org. Lett. 2012, 14, 1346).

EXAMPLE 27

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), (R)-1m (197.6 mg, 1.5 mmol), (R)-3a (254.0 mg, 1.0 mmol), and2e (169.2 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R,S_(a))-4me(153.4 mg, 67%) (eluent: petroleum ether/ethyl acetate=12/1) as aliquid: 98% de, >99% ee (major isomer) (HPLC conditions: Chiralcel OD-Hcolumn, hexane/i-PrOH=98/2, 1.0 mL/min, λ=214 nm, t_(R)(major)=13.4 min;[α]_(D) ²⁰=+73.0 (c=1.165, CHCl₃) (reported value: 93% de, >99% ee;[α]_(D) ²⁰=+60.8 (c=0.62, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.21(m, 5 H, ArH), 5.47-5.38 (m, 1 H, one proton from HC═C═CH), 5.37-5.30(m, 1 H, one proton from HC═C═CH), 5.19 (d, J=5.7 Hz, 1 H, PhCH), 2.40(s, 1 H, OH), 2.07-1.91 (m, 1 H, CH from Cy), 1.80-1.56 (m, 5 H, fiveprotons from Cy), 1.35-0.97 (m, 5 H, five protons from Cy); ¹³C NMR (75MHz, CDCl₃) δ 201.2, 143.2, 128.3, 127.5, 126.0, 100.8, 96.9, 72.3,37.1, 32.87, 32.85, 26.0, 25.9; IR (neat) ν (cm⁻¹) 3358, 3062, 3029,2924, 2850, 1961, 1602, 1493, 1449, 1015; MS (EI) m/z (%): 228 (M⁺,2.23), 107 (100). (reference: J. Ye, S. Li, B. Chen, W. Fan, J. Kuang,J. Liu, Y. Liu, B. Miao, B. Wan, Y. Wang, X. Xie, Q. Yu, W. Yuan, S. Ma,Org. Lett. 2012, 14, 1346).

EXAMPLE 28

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1n (106.0 mg, 1.5 mmol), (S)-3a (252.6 mg, 1.0 mmol), and 2e(168.4 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4ne (83.5 mg,50%) (eluent: petroleum ether/ethyl acetate=6/1) as a liquid: 96% ee(HPLC conditions: Chiralcel IC column, hexane/i-PrOH=100/1, 0.6 mL/min,λ=214 nm, t_(R)(minor)=20.5 min, t_(R)(major)=22.0 min); [α]_(D)²⁰=−84.5 (c=1.095, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.18-5.07 (m, 2 H,CH═C═CH), 3.70 (t, J=6.3 Hz, 2 H, OCH₂), 2.30-2.19 (m, 2 H, CH₂),2.05-1.89 (m, 1 H, CH from Cy), 1.89-1.57 (m, 6 H, OH and five protonsfrom Cy), 1.37-0.98 (m, 5 H, five protons from Cy); ¹³C NMR (75 MHz,CDCl₃) δ 203.4, 97.7, 88.0, 62.0, 37.1, 33.04, 33.02, 32.4, 26.1, 26.0;IR (neat) ν (cm⁻¹) 3340, 2924, 2851, 1961, 1448, 1049; MS (EI) m/z (%):166 (M⁺, 6.05), 67 (100); HRMS calcd for C₁₁H₁₈O [M⁺]: 166.1358; Found:166.1365.

EXAMPLE 29

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1o (313.4 mg, 1.5 mmol), (S)-3a (253.9 mg, 1.0 mmol), and 2e(167.8 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4oe (180.0 mg,59%) (eluent: petroleum ether/ethyl acetate=5/1) as a liquid: 98% ee(HPLC conditions: Chiralcel AD-H column, hexane/i-PrOH=95/5, 0.5 mL/min,λ=214 nm, t_(R)(major)=34.1 min, t_(R)(minor)=35.6 min); [α]_(D)²⁰=−102.0 (c=1.05, CHCl₃) (reported value: 99% ee; [α]_(D) ²⁰=−105.5(c=1.07, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 7.80-7.72 (m, 2 H, ArH),7.30 (d, J=7.8 Hz, 2 H, ArH), 5.21-5.12 (m, 1 H, one proton of CH═C═CH),5.11-5.01 (m, 1 H, one proton of CH═C═CH), 4.85 (t, J=5.9 Hz, 1 H, NH),3.60-3.50 (in, 2 H, NCH₂), 2.42 (s, 3 H, CH₃), 1.98-1.82 (m, 1 H, CHfrom Cy), 1.73-1.53 (m, 5 H, five protons from Cy), 1.32-0.89 (m, 5 H,five protons from Cy); ¹³C NMR (75 MHz, CDCl₃) δ 202.3, 143.3, 137.0,129.6, 127.0, 100.4, 88.4, 42.0, 36.7, 32.8, 32.7, 25.9, 25.8, 21.4; IR(neat) ν (cm⁻¹) 3284, 2924, 2850, 1962, 1598, 1495, 1418, 1329, 1161,1094; MS (EI) m/z (%): 305 (M⁺, 1.14), 91 (100). (reference: J. Ye, W.Fan, S. Ma, Chem. Eur. J. 2013, 19, 716).

EXAMPLE 30

Following the procedure of Example 17. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1p (238.4 mg, 1.5 mmol), (S)-3a (254.3 mg, 1.0 mmol), and 2d(129.9 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4pd (136.8 mg,59%) (eluent: petroleum ether/ethyl acetate=5/1) as a liquid: 93% ee(HPLC conditions: Chiralcel AY-H column, hexane/i-PrOH=90/10, 1.0mL/min, λ=214 nm, t_(R)(major)=9.8 min, t_(R)(minor)=11.2 min); [α]_(D)²⁰=−92.5 (c=0.78, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.82-7.73 (m, 2 H,ArH), 7.51-7.35 (m, 3 H, ArH), 6.52 (bs, 1 H, NH), 5.30-5.19 (m, 2 H,CH═C═CH), 4.05-3.95 (m, 2 H, NCH₂), 1.96-1.86 (m, 2 H, CH₂), 1.73-1.55(m, 1 H, CH), 0.894 (d, J=6.6 Hz, 3 H, Me), 0.891 (d, J=6.6 Hz, 3 H,Me); ¹³C NMR (75 MHz, CDCl₃) δ 203.8, 167.3, 134.5, 131.3, 128.4, 126.8,92.9, 87.8, 38.5, 38.0, 28.3, 22.1, 22.0; IR (neat) ν (cm⁻¹) 3320, 3064,2955, 2927, 2869, 1964, 1727, 1644, 1603, 1578, 1538, 1489, 1465, 1308,1076; MS (EI) m/z (%): 229 (M⁺, 7.05), 105 (100); HRMS calcd forC₁₅H₁₉NO [M⁺]: 229.1467; Found: 229.1469.

EXAMPLE 31

Following the procedure of Example 17. The reaction of CuBr₂ (44.9 mg,0.2 mmol), 1q (232.8 mg, 1.5 mmol), (S)-3a (253.2 mg, 1.0 mmol), and 2i(150.6 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4qi (160.3 mg,67%) (eluent: petroleum ether/ethyl acetate=50/1 to petroleumether/ethyl acetate=20/1) as a liquid: 96% ee (HPLC conditions:Chiralcel OD-H column, hexane/i-PrOH=100/0, 1.0 mL/min, λ=214 nm,t_(R)(minor)=19.7 min, t_(R)(major)=20.4 min); [α]_(D) ²⁰=−63.5(c=1.055, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.22-5.12 (m, 1 H, oneproton of CH═C═CH), 5.11-5.03 (m, 1 H, one proton of CH═C═CH), 4.71 (bs,1 H, NH), 3.77-3.63 (m, 2 H, NCH₂), 1.93-1.78 (m, 1 H, CH), 1.53-1.21(m, 13 H, Me×2 and CH₂×2), 0.90 (t, J=7.4 Hz, 3 H, Me), 0.89 (t, J=7.4Hz, 3 H, Me); ¹³C NMR (75 MHz, CDCl₃) δ 203.0, 155.6, 97.7, 89.0, 79.1,42.7, 39.3, 28.3, 27.5, 27.2, 11.6, 11.4; IR (neat) ν (cm⁻¹) 3351, 2965,2931, 2875, 1963, 1698, 1505, 1456, 1392, 1366, 1250, 1172, 1053; MS(EI) m/z (%): 239 (M⁺, 0.01), 183 ((M−^(t)Bu+H)⁺, 45.91), 57 (100); HRMScalcd for C₁₄H₂₅NO₂ [M⁺]: 239.1885; Found: 239.1878.

EXAMPLE 32

Following the procedure of Example 17. The reaction of CuBr₂ (45.0 mg,0.2 mmol), 1r (255.7 mg, 1.5 mmol), (5)-3a (252.5 mg, 1.0 mmol), and 2d(129.6 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4rd (121.9 mg,51%) (eluent: petroleum ether/ethyl acetate=20/1) as a liquid: 94% ee(HPLC conditions: Chiralcel OD-H column, hexane/i-PrOH=100/1, 0.7mL/min, λ=214 nm, t_(R)(minor)=10.9 min, t_(R)(major)=11.7 min); [α]_(D)²⁰=−64.4 (c=0.87, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 5.15-5.04 (m, 2 H,CH═C═CH), 3.74 (s, 6 H, Me×2), 3.51 (t, J=7.5 Hz, 1 H, CFI), 2.62-2.54(m, 2 H, CH₂), 1.90-1.82 (m, 2 H, CH₂), 1.72-1.56 (m, 1 H, CH), 0.910(d, J=6.6 Hz, 3 H, Me), 0.906 (d, J=6.6 Hz, 3 H, Me); ¹³C NMR (75 MHz,CDCl₃) δ 204.6, 169.3, 169.2, 91.3, 86.6, 52.4, 51.3, 38.2, 28.3, 28.0,22.09, 22.06; IR (neat) ν (cm⁻¹) 2956, 2927, 2869, 1964, 1754, 1739,1436, 1342, 1271, 1232, 1154, 1044; MS (EI) m/z (%): 240 (M⁺, 27.06), 97(100); HRMS calcd for C₁₃H₂₀O₄ [M⁺]: 240.1362; Found: 240.1362.

EXAMPLE 33

Following the procedure of Example 17. The reaction of CuBr₂ (44.8 mg,0.2 mmol), 1r (255.7 mg, 1.5 mmol), (5)-3a (252.8 mg, 1.0 mmol), and 2e(168.2 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4re (135.7 mg,51%) (eluent: petroleum ether/ethyl acetate=15/1) as a liquid: 95% ee(HPLC conditions: Chiralcel OD-H column, hexane/i-PrOH=100/1, 1.0mL/min, λ=214 nm, t_(R)(minor)=9.0 min, t_(R)(major)=9.6 min); [α]_(D)²⁰=−84.0 (c=1.045, CHCl₃) (reported value: 99% ee; [α]_(D) ²⁰=−85.4(c=1.05, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 5.20-5.08 (m, 2 H, CH═C═CH),3.740 (s, 3 H, Me), 3.737 (s, 3 H, Me), 3.51 (t, J=7.5 Hz, 1 H, CH),2.63-2.54 (m, 2 H, CH₂), 2.00-1.85 (m, 1 H, CH from Cy), 1.78-1.57 (m, 5H, five protons from Cy), 1.35-0.95 (m, 5 H, five protons from Cy); ¹³CNMR (75 MHz, CDCl₃) δ 202.7, 169.33, 169.29, 98.9, 88.2, 52.4, 51.2,37.1, 32.82, 32.78, 28.0, 26.0, 25.9; IR (neat) ν (cm⁻¹) 2926, 2851,1959, 1757, 1738, 1617, 1436, 1343, 1233, 1155, 1035; MS (EI) m/z (%):266 (M⁺, 6.72), 91 (100). (reference: J. Ye, W. Fan, S. Ma, Chem. Eur.J. 2013, 19, 716).

EXAMPLE 34

Following the procedure of Example 17. The reaction of CuBr₂ (44.9 mg,0.2 mmol), is (207.8 mg, 1.5 mmol), (S)-3a (253.4 mg, 1.0 mmol), and 2c(201.5 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4sc (119.3 mg,47%) (eluent: petroleum ether) as a liquid: 90% ee (HPLC conditions:Chiralcel OD-H column, hexane/i-PrOH=100/0, 0.3 mL/min, λ=214 nm,t_(R)(minor)=17.9 min, t_(R)(major)=19.7 min); [α]_(D) ²⁰=−50.0 (c=0.84,CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ 7.30-7.21 (m, 2 H, ArH), 7.21-7.12 (m,3 H, ArH), 5.16-5.02 (m, 2 H, CH═C═CH), 2.72 (t, J=7.8 Hz, 2 H, CH₂),2.35-2.20 (m, 2 H, CH₂), 1.99-1.87 (m, 2H, CH₂), 1.42-1.18 (m, 12 H,CH₂×6), 0.88 (t, J=6.8 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃) δ 204.0,141.9, 128.5, 128.2, 125.8, 91.5, 90.2, 35.5, 31.9, 30.7, 29.4, 29.3,29.2, 29.1, 28.9, 22.7, 14.1; IR (neat) ν (cm⁻¹) 3086, 3063, 3027, 2924,2854, 1962, 1721, 1604, 1496, 1455, 1373, 1331, 1284, 1075, 1028; MS(EI) m/z (%): 256 (M⁺, 12.85), 91 (100); HRMS calcd for C₁₉H₂₈ [M⁺]:256.2191, found: 256.2194.

EXAMPLE 35

Following the procedure of Example 17. The reaction of CuBr₂ (44.8 mg,0.2 mmol), 1t (153.2 mg, 1.5 mmol), (S)-3a (253.1 mg, 1.0 mmol), and 2e(168.4 mg, 1.5 mmol) in dioxane (3.0 mL) afforded (R_(a))-4te (90.1 mg,46%) (eluent: petroleum ether) as a liquid: 96% ee (HPLC conditions:Chiralcel OD-H column, hexane/i-PrOH=100/0, 0.3 mL/min, λ=214 nm,t_(R)(major)=20.1 min, t_(R)(minor)=22.1 min); [α]_(D) ²⁰=−355.3(c=1.01, CHCl₃) (reported value: 99% ee; [α]_(D) ¹⁹=−330.3 (c=0.94,CHCl₃)) (The results we repeated the reaction in ref. 3: 99% ee; [α]_(D)²⁰=−379.0 (c=1.125, CHCl₃)); ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.23 (m, 4H, ArH), 7.21-7.11 (m, 1 H, ArH), 6.15 (dd, J₁=6.6 Hz, J₂=3.0 Hz, 1 H,one proton from CH═C═CH), 5.56 (t, J=6.3 Hz, 1 H, one proton fromCH═C═CH), 2.20-2.04 (m, 1 H, CH), 1.90-1.57 (m, 5 H, five protons fromCy), 1.38-1.09 (m, 5 H, five protons from Cy); ¹³C NMR (75 MHz, CDCl₃) δ204.1, 135.2, 128.5, 126.6, 126.4, 101.0, 95.4, 37.6, 33.2, 33.1, 26.1,26.0; IR (neat) ν (cm⁻¹) 3082, 3062, 3030, 2924, 2851, 1946, 1597, 1496,1458, 1257, 1071, 1028; MS (EI) m/z (%): 198 (M⁺, 30.22), 130 (100).(reference: R. Lü, J. Ye, T. Cao, B. Chen, W. Fan, W. Lin, J. Liu, H.Luo, B. Miao, S. Ni, X. Tang, N. Wang, Y. Wang, X. Xie, Q. Yu, W. Yuan,W. Zhang, C. Zhu, S. Ma, Org. Lett. 2013, 15, 2254).

Finally, it should be noted that the above mentioned is just only somespecific examples of the present invention. Obviously, the presentinvention is not limited to the above examples, which can have manyvariations. All the modifications derived directly or envisaged by aperson skilled in the art from the disclosure of the present inventionshall fall within the scope of the present invention.

What is claimed:
 1. A process for synthesizing optically active1,3-disubstituted allenes, in a heated reaction comprising afunctionalized terminal alkyne, an aldehyde and a chiral secondary amineas reactants, a divalent copper salt as a catalyst and an organicsolvent, thereby producing a variety of functionalized axially chiral1,3-disubstituted allenes; wherein the process consists of: adding insequence to a reaction under nitrogen atmosphere: a divalent coppersalt, a chiral secondary amine, a terminal alkyne, an aldehyde and anorganic solvent; subjecting the reaction to anhydrous and anaerobictreatment by heating for 12-24 h in an oil bath; returning the reactionto room temperature, diluting the reaction with the organic solvent,washing the reaction with dilute hydrochloric acid, separating theorganic phase, extracting the aqueous phase with the organic solvent,washing with saturated brine, drying with anhydrous sodium sulfate,filtering, concentrating and subjecting reaction products to columnchromatography, so as to obtain the axially chiral allene; wherein thereaction has a following reaction equation:

wherein R¹ comprises functional groups selected from glycosidic units,primary alcohols, secondary alcohols, tertiary alcohols, amides,malonates, alkyl group or aryl group, and R² is an alkyl group or anaryl group.
 2. The process for synthesizing optically active1,3-disubstituted allenes of claim 1, wherein the catalyst is copperbromide, copper chloride, copper acetate, copper sulfate or coppertriflate.
 3. The process for synthesizing optically active1,3-disubstituted allenes of claim 1, wherein the chiral secondary amineis selected from the group consisting of (S)-3a and enantiomers thereof:


4. The process for synthesizing optically active 1,3-disubstitutedallenes of claim 1, wherein the organic solvent is 1,4-dioxane, toluene,benzene, chlorobenzene, p-xylene, o-xylene, m-xylene, or mesitylene. 5.The process for synthesizing optically active 1,3-disubstituted allenesof claim 3, wherein the organic solvent is 1,4-dioxane, toluene,benzene, chlorobenzene, p-xylene, o-xylene, m-xylene, or mesitylene.